WO2013132206A1

WO2013132206A1 - Biological fluid monitoring device

Info

Publication number: WO2013132206A1
Application number: PCT/GB2013/000088
Authority: WO
Inventors: Kar Seng TENG; Jonathan Lloyd
Original assignee: Swansea University
Priority date: 2012-03-06
Filing date: 2013-03-04
Publication date: 2013-09-12
Also published as: GB201203977D0; GB2500176A

Abstract

A biological fluid monitoring device is shown generally as 1 in Figure 1. The device consists of microneedles (20) to take up a biological fluid from an individual, a reservoir (30) for receiving the fluid and a sensor (40), associated with microstructures (41), that is housed within the reservoir and which analyzes the blood components and composition. The device is connected to transmitter (51) which can send data in real time about analytes that are being monitored in the biological fluid.

Description

Biological Fluid Monitoring Device

Field of the Invention

The present invention relates to a biological fluid monitoring device and in particular but not exclusively to a blood monitoring device that is non-invasive and which in particular monitors the glucose level of an individual.

Background of the Invention

Previously blood was taken by individuals trained to take blood samples, and this was often in a hospital environment, the blood would then be sent to a laboratory facility for analysis. Such procedures were costly because of the need for highly trained individuals and the use of special facilities such as clinics where the samples could be taken and analysed. In addition because there are several steps in the process, it means that individuals have to wait for their results and there is no opportunity to make a real time analysis of the blood sample.

More recently, individuals can take their own blood and special instruments are available for determining blood glucose levels in people with diabetes. The technology uses a small blood sample, obtained from a finger prick. The blood is placed on chemically prepared strips and inserted into a portable instrument which analyses it and provides a blood glucose level measurement. Diabetics must prick their fingers to draw blood for monitoring their glucose levels and some of them must do this many times a day. This can be distressing to the individual.

Non-invasive methods of blood monitoring have been developed such as non-invasive optical methods for measuring sugar in blood and instruments used in these methods use absorption, transmission, reflection or luminescence methods for spectroscopically analysing blood glucose concentrations. US 5,515,847 and US 5,615,672 show a method and apparatus for monitoring glucose, ethyl alcohol and other blood constituents in a non-invasive manner. The measurements are made by monitoring infrared absorption of the desired blood constituent in the long infrared wavelength range where the blood constituent has a strong and distinguishable absorption spectrum. US 5,666,956 shows an instrument and method for non-invasive monitodng of human body tissue analytes by measuring the body's infrared radiation e.g. emission spectral lines characteristic to tissue analytes. It is based on the discovery that natural infrared emission from the human body, especially from the tympanic membrane (which has the properties of a blackbody cavity), is modulated by the state of the emitting tissue. Spectral emissivity of infrared radiation from the tympanic membrane consists of spectral information of the blood analyte. This spectral emissivity is measured as heat emitted by the body and can be directly correlated with the blood analyte concentration, for example, the glucose concentration.

These known devices have limitations, for example where near infrared light is used for measurement of absorption, transmission or reflectance; one can observe interference in absorption from other chemical components. Analyses based on only one or two wavelengths can be inaccurate if there is alcohol in the blood or any other substances that absorb at the same frequencies. In addition, these analyses can be thrown off by instrument errors, (samples with spectra that differ from the calibration set) physiological differences between people (skin pigmentation, thickness of the finger). Since the amount of glucose in the body is less than one thousandth that of other chemicals (and all of them possess absorption in the near infrared), variations of these constituents, which exist among people, may make universal calibration unlikely.

The present invention seeks to overcome the problems associated with the prior art by providing an accurate and continual way of monitoring blood, with minimal impact on the individual that is being monitored. The apparatus and method involves obtaining blood, lymph, Or interstitial fluid more quickly, using an easier procedure, and relatively noninvasively. Furthermore, the invention allows for real time evaluation of biological fluids in a minimally-invasive, painless, and convenient manner.

Summary of the Invention

According to the invention there is provided a device for the continuous monitoring of biological fluid from an individual, said device comprising an array of microneedles arranged to contact the skin of an individual, said microneedles being in communication with a reservoir that allows for the flow of extracted biological fluid to a sensor in fluid communication with the reservoir, characterized in that there is a plurality of nanostructures extending from a surface area associated with the sensor to provide an increased sensitivity for the device when monitoring one or more anayltes in the biological fluid.

The nanostructures are preferably elongate structures where the width of the nanostructures is measured in nanometers but the length of the structures may be measured in nanometers or micrometres.

Preferably the biological fluid is blood or interstitial fluid.

It is envisaged that at least one of the anayltes in the biological fluid is glucose.

Preferably the nanostructures are Zinc Oxide nanowires or nanorods. in a preferred arrangement the nanostructures are aligned nanowires

It is envisaged that device is provided as a disposable component that can be reJeasably attached to controls for the sensor. The controls are typically potentiometric electronics.

Preferably the device is secured to a transmitter that can send data that is being received from the sensor to a remote receiver so that real time data about the analytes in the biological fluid can be recorded.

It is envisaged that the real time data is transmitted using wireless communication, e.g. Bluetooth technology.

Preferably the device is attached to an accelerometer. The accelerometer monitors movement of the wearer and if there is no movement for a defined period of time or if there is a sudden sharp change in movement (i.e. as a result of a fall due to fainting) a warning can be sent out. If there is no movement then this may indicate that an individual has fainted and this often occurs when an individual's glucose is low and so they are in danger of hypoglycaemia attack.

In the event of hypoglycaemia attack (i.e. when the glucose level is low and no movement is detected), an emergency signal will be transmitted from the remote sensor to a receiver, which can be a mobile communication device. This communication device will then send out alert messages to either emergency personnel or friends and relatives of the patients to provide medical attention.

Preferably the sensor has three electrodes, a working, counter and reference electrodes held on a flexible substrate, which is preferably a polymer substrate.

It is envisaged that the nanostructures are grown from a seed layer on the working electrode.

It is envisaged that the nanowires are grown using hydrothermal growth technique on a polymer substrate.

It is envisage that printing techniques can be used to fabricate the three electrodes sensor and print the nanostructure seed materials selectively on the working electrode. This technique is cost-effective and is suitable for large-scale production of the sensors.

In a preferred arrangement the nanostructures are functionalized with one or more receptors to detect the presence of a target in the analyte. For the detection of blood glucose, enzymes (i.e. glucose oxidase) will be used as a receptor for the detection of glucose in the analyte.

It is envisaged that the technology is particularly useful to measure diabetes but it can be used for monitoring other chronic diseases, such as heart diseases, stroke, chronic obstructive pulmonary diseases, asthma and cancers etc., through the use of an appropriate receptor at the surface of the nanostructures.

Brief Description of the Drawings An embodiment of the invention will now be described by way of example only with reference to and as illustrated in the accompanying Figures in which:

Figure 1 shows: a sensor according to an embodiment of the invention;

Figure 2 shows: an array of nanostructures; and

Figure 3 shows: the arrangement of the electrodes used with the sensor shown in Figure J . Detailed Description of the Invention

A biological fluid monitoring device is shown generally as 1 in Figure 1. The device includes microneedles 20 to take up biological fluid, such as blood from an individual, a reservoir 30 for receiving the fluid and a sensor 40 that is housed within the reservoir and which analyzes the blood components and composition. The sensor 40 has nanostructures 41 associated with an electrode for the sensor and these nanostructures having large surface to volume ratio increases the sensitivity of the sensor as the biological fluid passes by when flowing through the reservoir. Also by having an increased surface area that is formed from nanostructures, the device itself can be kept as small as possible. The reservoir 30 is made up of two parts, a channel 31 through which fluid flows to a reservoir 32 where the sensor is positioned.

The device itself forms a first part of a monitoring system and this first part is attached to a second part that is formed of the controls 50 for the sensor and also a transmitter 51 which receives and forwards data from the sensor and which controls and monitors the sensor periodically, transmitting information such as glucose levels and/or warnings to an external mobile device.

Furthermore, there is a built-in accelerometer 52 in the sensor electronics for the detection of movement/consciousness and fall of the user. The whole device is then covered with an adhesive patch 60 to keep the device tight to the skin and watertight.

The microneedles 20 typically provide as an array that can come into contact with the body. The microneedles allow for the uptake of interstitial fluid from under the surface of the skin. The length of the needles will be sub 250 um meaning the device will be entirely painless as the microneedles are sized to avoid or minimize contact with nerve endings in the biological tissue, such as the dermis, thereby eliminating or reducing pain when the microneedles are inserted, for example into the skin. The microneedles are attached to a substrate 21 to which the base of the microneedle(s) is secured or integrated, and at least one reservoir/fluid collection chamber 30 and/or sensor 40 is in communication with the array of microneedles.

Typically, the microneedles 20 are a two-dimensional array of three-dimensional needle structures, in contrast to a device with a single needle or row of needles. The blood monitoring device can be constructed from a variety of materials, including metals, ceramics,

semiconductors, organics, polymers, and composites. The microneedles function either as a conduit, a sensing element, or a combination thereof. Conduit microneedles can have a porous or hollow shaft. As used herein, the term "porous" means having pores or voids throughout at least a portion of the microneedle structure, sufficiently large and sufficiently interconnected to permit passage of fluid and/or solid materials through the microneedle. As used herein, the term

"hollow" means having one or more substantially annular bores or channels through the interior of the microneedle structure, which have a diameter sufficiently large to permit passage of fluid and/or solid materials through the microneedle.

Transportation of molecules through the microneedles can be controlled or monitored using, for example, various combinations of semi-permeable membranes, valves, pumps, sensors, actuators, and microprocessors. These components can be produced using standard

manufacturing or microfabrication techniques. Actuators that may be useful with the

microneedle devices disclosed herein include micropumps, microvalves, and positioners.

In a preferred embodiment, the microneedle device is used in combination with another mechanism that enhances the permeability of the biological barrier, for example by increasing cell membrane disruption, using electric fields, ultrasound, chemical enhancers, vacuum, viruses, pH, heat, and/or light. Chemical and/or physical enhancers can be applied to the biological barrier at the site of insertion of the device before or during the withdrawal of the device, for example, to draw analyte closer to the skin surface (or into a container adapted for the particular analytical method to be employed).

The microneedles of the device can be constructed from a variety of materials, including metals, ceramics, semiconductors, organics, polymers, and composites. Preferred materials of

construction include pharmaceutical grade stainless steel, gold, titanium, nickel, iron, tin, chromium, copper, palladium, platinum, alloys of these or other metals, silicon, silicon dioxide, and polymers. Representative biodegradable polymers include polymers of hydroxy acids such as lactic acid and glycolic acid polylactide, polyglycolide, polylactide-co-glycolide, and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly( valeric acid), and poly(lactide-co-caprolactone). Representative non-biodegradable polymers include polycarbonate, polymethacrylic acid, ethylenevinyl acetate,

polytetrafluoroethylene (TEFLON(TM)), and polyesters. A preferred material that is used is a polyimide. The microneedles can be oriented perpendicular or at an angle to the substrate. Preferably, the microneedles are oriented perpendicular to the substrate to provide structural strength and to permit ease of insertion into the tissue. An array of microneedles can include a mixture of microneedle orientations, heights, spacings, or other parameters. This variation in an array can be useful, for example, if different microneedles are to provide different sensing or insertion functions.

The fluid collection chamber/reservoir 30 is selectably in connection with the microneedle bores or pores, such that a biological fluid can flow from the tissue surrounding the microneedle, through the microneedle, and into the collection chamber. Typically, the collection chamber is attached to, or integrated into, the substrate. The chamber should fijnction to contain a biological fluid sample so as to permit analysis within the microneedle device or following transfer to a separate analytical device. The collection chamber can be substantially rigid or readily deformable. The collection chamber can be formed from one or more polymers, metals, ceramics, semiconductor, or combinations thereof. In a preferred embodiment, there is a porous or absorbent material, such as a sponge, gel, or paper or polymeric strip that can collect biological fluid that has passed through the device. This material may be in the collection chamber or it may be in a separate chamber that is downstream of the collection chamber. The material can be permanently contained or removable, and can function as a diagnostic element or substrate for use in analytical devices. The chamber can initially be empty or can contain a gas or one or more reagents in any form (e.g., liquid or solid particles). In one embodiment, at least a portion of the interior walls of the chamber are coated with a reagent for assaying the biological fluid. The fluid collection chamber/reservoir 30 includes a sems of nanostructures 41, which typically are grown from an electrode on an electrode support 74 that can be attached to surface 70 of the sensor and in effect forms part of the sensor 40. The nanostructures are preferably in the form of aligned wires as shown in Figure 2. The nanostructures are grown using hydrothermal technique from a seed layer on the electrodes that are positioned on the plastic support 74 and typically the electrodes are printed onto this support.

Typically the sensor includes three electrodes positioned on the electrode support and these are a working electrode (WE) 71, a counter electrode (CE) 72 and reference electrode (RE) 73. The working electrode 71 of the sensor 40 consists of nanomaterials such as nanowires, nanorods and nano-clusters etc. Preferably the nanostructures are in alignment so as to provide the maximum area possible for the device, which results in an increased sensitivity for the sensor. The electrodes may be printed directly onto a chip or they may be printed onto a material such as an electrode support that is then adhered to a chip. If a support is used, the electrode support 74 is a polymer substrate and the electrodes can be incorporated onto the polymer using cost-effective printing techniques. Further the sensor and nanostructures, which between them provide what could be described as a "sensor chip" can be used to detect other chronic diseases by

functionalising the nanomaterials with an appropriate biomarker.

Although a three electrode system is used because current is being measured, it is possible to have a two electrode system and such a system is a voltametric system where potential is measured and there is no counter electrode.

The nanostructures are typically composed of Zinc Oxide (ZnO) and are grown on to the working electrode, which typically is a gold electrode coated with a ZnO seed layer using hydrothermal growth techniques. For example where the nanostructures are nanowires, they are grown from the deposited ZnO seed layer which results in a highly ordered array of ZnO nanowires. The nanowires provide not only an extremely high surface area on the working electrode and a biocompatible surface for functionalisation with enzymes but also result in excellent sensitivity, reliability and response rate in the continuous blood glucose monitor (CBGM). The sensor chip, having an area of approximately 1 1 x 5 mm, and the support 74 is a polymer such as a polymer (i.e. Polyimide) substrate. The support can be adhered to the surface of the sensor 70 as shown in Figure 1. The disposable sensor, reservoir and microneedles can be detached from the more expensive electronic controls and disposed of, which again makes this system a very cost effective and safe system as any part that comes in contact with the individual can be disposed of.

Having the nanowires in alignment means that there is the maximum surface area available for the sensor, making it more sensitive. The cavity, fluid communication with sensor 40, is a continuous blood glucose monitoring (CBGM) sensor. The sensor communicates when in use with a transmitter 50 and this allows for the continuous relaying of data to a receiver about the properties of the blood that is being samples. In a preferred embodiment, the sensors are selectively in communication with an electronics package. The electronics package typically includes a power source (e.g., a battery), as well as electronic hardware and software for the transduction, storage, transmission, and display of measured values. The electronics package can be selectively fixed to the microneedle device, for example, so that the electronics package can be reused with a new, disposable microneedle device. The electronics package can include a mechanism for wireless or wire-based transmission of measured values to a remote device for analysis and/or display. The electronics also may include mathematical manipulation of the sensed data, for example, to average measured values or eliminate outlying datapoints so as to provide more useful measurements. This manipulation could also include prediction of trends over time.

The electronics package also can include software and hardware to initiate or automate the sensing and analysis processes.

Calibration of the sensor can be accomplished using the concentration of a second analyte or the same analyte measured by another means. The primary analyte can be normalized, lowering extraction to extraction and site to site variability, by the concentration of the second analyte or same analyte from a separate measurement. Normalization may be a linear or non-linear relationship. In a preferred embodiment for glucose sensing, a reusable sensor, which assays glucose concentration in interstitial fluid, can be calibrated daily by correlating interstitial fluid glucose values with values obtained from glucose measurements obtained from blood.

The microneedles, sensor and nanostructures all form one part of the device which is disposable. This part of the device can be releasably secured to the electronics of the sensor and a transmitter which can be used on a repeated basis with microneedles that have been replaced.

The device will be attached to the individual by way of an adhesive patch or plaster when the microneedles, reservoir and sensor have been secured to the sensor electronics and transmitter.

The devices disclosed herein are useful in the transport of biological fluids from within or across a variety of biological barriers including the skin (or parts thereof); the blood-brain barrier; mucosal tissue; blood vessels; lymphatic vessels; cell membranes; epithelial tissue; and endothelial tissue. The biological barriers can be in humans or other types of animals, as well as in plants, insects, or other organisms, including bacteria, yeast, fungi, and embryos. In preferred embodiments, biological fluids are withdrawn from skin, more preferably human skin, for minimally invasive diagnostic sensing. Biological fluids useful with the devices described herein include blood, lymph, interstitial fluid, and intracellular fluid. In a preferred embodiment, the biological fluid to be withdrawn or sensed is interstitial fluid.

A variety of analytes are routinely measured in the blood, lymph or other body fluids. Examples of typical analytes that can be measured include blood sugar (glucose), cholesterol, bilirubin, creatine, various metabolic enzymes, hemoglobin, heparin, hematocrit, vitamin K or other clotting factors, uric acid, carcinoembryonic antigen or other tumor antigens, and various reproductive hormones such as those associated with ovulation or pregnancy. Other substances or properties that would be desirable to detect include lactate (important for athletes), oxygen, pH, alcohol, tobacco metabolites, and illegal drugs (important for both medical diagnosis and law enforcement). With the use of an appropriate receptor at the surface of the nanostructures, the technology can be applied to monitor other chronic diseases, such as heart diseases, stroke, chronic obstructive pulmonary diseases and asthma etc. It is to be understood that the above embodiments have been provided only by way of exemplification of this invention, such as those detailed below, and that further modifications and improvements thereto, as would be apparent to persons skilled in the relevant art, are deemed to fall within the broad scope and ambit of the present invention described. Furthermore where individual embodiments are discussed, the invention is intended to cover combinations of those embodiments as well.

Claims

1. A device for the continuous monitoring of biological fluid from an individual, said device comprising an array of microneedles, said microneedles being arranged to contact the skin of an individual, said microneedles being in communication with a reservoir that allows for the flow of extracted biological fluid to a sensor in fluid communication with the reservoir, characterized in that there is a plurality of nanostructures extending from a surface area associated with the sensor to provide an increased sensitivity for the sensor- when monitoring one or more anayltes in the biological fluid.

2. A device according to claim 1 wherein the biological fluid is blood or interstitial fluid.

3. A device according to claim 1 or claim 2 wherein at least one of the anayltes in the

biological fluid is glucose.

4. A device according to any preceding claim wherein the nanostructures are formed from a Zinc Oxide.

5. A device according to any of claims 1 to 4 wherein the sensor has two electrodes, a

working and a reference electrode.

6. A device according to any of claims 1 to 4 wherein the sensor has three electrodes, a

working, counter and reference electrode.

7. A device according to claim 5, or claim 6 wherein the nanostructures are grown from a seed layer the working electrode.

8. A device according to any preceding claim wherein the nanostructures are functionalized for the detection of analyte.

9. A device according to any preceding claim wherein the nanostructures are nanowires arranged in vertical alignment with one another.

10. A device according to any preceding claim which is releasably securable to a control system, said control system including controls for the sensor and a transmitter.

1 1. A device according to any preceding claim wherein the control system includes an accelerometer attached thereto.

12. A device according to claim 10 or claim 1 1 wherein data from the transmitter or

accelerometer is transmitted using wireless communication.

13. A device according to claim 12, wherein data is being transmitted in real time.

14. A monitoring system provided by a device according to any of claims 1 to 9 in

combination with a control system including controls for the sensor, a transmitter and an accelerometer.

15. A monitoring system according to claim 14 including a receptor on the nanostructures, said momtoring system being arranged to monitor heart diseases, stroke, chronic obstructive pulmonary diseases or asthma.

16. A device as substantially described herein with reference to and as illustrated in the accompanying figures.

17. A monitoring system as substantially described herein with reference to and as illustrated in the accompanying figures